Adenosine A 3 Receptor Expression and Function in Mitochondria

Mitochondrial dysfunction is emerging as a common mechanism of a variety of neurodegenerative diseases, including chemotherapy‐induced neuropathic pain. We have recently found that administration of selective agonists to the G protein‐coupled, adenosine A 3 receptor (A 3 AR) prevents the development of chemotherapy‐induced mitochondrial dysfunction in peripheral sensory neurons that result peripheral neuropathy and chronic pain. Recent evidence also indicates the presence of G proteins and G‐coupled protein receptors within mitochondria, including the adenosine A 1 and A 2A receptors. Bioinformatic analysis revealed potential mitochondrial‐associated sequences in published A 3 AR protein sequences, thus prompting us to hypothesize that A 3 AR is associated with mitochondria and its signaling could regulate mitochondrial function. Using Western blot analysis and transmission immune‐electron microscopy, we report for the first time that A 3 AR is present in normal rat mitochondria purified from liver, spinal cord and peripheral blood lymphocytes. Moreover, we also report that when normal rodent mitochondria are pretreated with the selective A 3 AR agonist, MRS5890, they produced more ATP following ADP‐stimulation than mitochondria treated with its vehicle (0.002% DMSO). We also find that MRS5980 counteracts normal mitochondrial membrane depolarization during calcium mobilization. Collectively, our data provide the first evidence for the presence A 3 AR in mitochondria and initial mechanistic insight to its functional role in mitochondria that potentially could serve as a target for the treatment of neurodegenerative disease. Support or Funding Information NIH‐NCI CA169519